title: CAMKII and calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16.
abstract: The insulin-like signaling pathway maintains a relatively short wild-type lifespan in Caenorhabditis elegans by phosphorylating and inactivating DAF-16, the ortholog of the FOXO transcription factors of mammalian cells. DAF-16 is phosphorylated by the AKT kinases, preventing its nuclear translocation. Calcineurin (PP2B phosphatase) also limits the lifespan of C. elegans, but the mechanism through which it does so is unknown. Herein, we show that TAX-6•CNB-1 and UNC-43, the C. elegans Calcineurin and Ca(2+)/calmodulin-dependent kinase type II (CAMKII) orthologs, respectively, also regulate lifespan through DAF-16. Moreover, UNC-43 regulates DAF-16 in response to various stress conditions, including starvation, heat or oxidative stress, and cooperatively contributes to lifespan regulation by insulin signaling. However, unlike insulin signaling, UNC-43 phosphorylates and activates DAF-16, thus promoting its nuclear localization. The phosphorylation of DAF-16 at S286 by UNC-43 is removed by TAX-6•CNB-1, leading to DAF-16 inactivation. Mammalian FOXO3 is also regulated by CAMKIIA and Calcineurin. DOI:http://dx.doi.org/10.7554/eLife.00518.001.
authors.affiliation: Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China ; National Institute of Biological Sciences, Beijing , Beijing , China.
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.forename: Yue-He
authors.initials: YH
authors.lastname: Ding
authors.forename: Shang-Tong
authors.initials: ST
authors.lastname: Li
authors.forename: Shengyi
authors.initials: S
authors.lastname: Peng
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Dan
authors.initials: D
authors.lastname: Tan
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
authors.forename: Meng-Qiu
authors.initials: MQ
authors.lastname: Dong
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism / Q000502:physiology*; D019703:Calcineurin / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D051858:Forkhead Transcription Factors; D018384:Oxidative Stress; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin
keywords: C. elegans; CAMKII; DAF-16; FOXO; aging; calcineurin; lifespan